DESC:
The present invention is to provide a single-pot process to synthesize the latent acid diol linker followed by in-situ polymerization reaction for preparing POE-IV based copolymers having a structural formula of Formula I including TEG-POE IV based copolymers.

Formula I

According to one embodiment, the present invention provides a process for preparing POE-IV polymers represented in Formula II comprising the steps of

Formula II

(a) dissolving excess TEG (or any dihydroxy alkyl compounds) and glycolide in an organic solvent at elevated temperature under inert atmosphere to form the latent acid hydroxy-based linkers;
(b) dissolving DETOSU monomer in an organic solvent to form a separate monomer solution;
(c) after formation of the latent acid hydroxy-based linker in step a, adding the DETUSO monomer solution to start the polymerization reaction; and
(d) stirring the solutions under inert atmosphere and high speed at room temperature to produce polymer.

According to another embodiment, the present invention provides a process for preparing polymers TEG POE-IV represented in Formula II comprising the steps of

Formula II

(a) dissolving excess TEG and glycolide in an organic solvent at elevated temperature under inert atmosphere to form the glycolic acid diol linker;

wherein m is between 2 and 7.

(b) dissolving DETOSU monomer in an organic solvent to form a separate monomer solution;

(c) after formation of the latent acid hydroxy-based linker in step a, adding the DETUSO monomer solution to start the polymerization reaction; and

wherein m is between 2 and 7; n is between 3 and 40; p is between 15 and 100.

(d) stirring the solutions under inert atmosphere and high speed to produce polymer.

In TEG POE-IV represented in Formula III, R, R`, R``refers to a branched or unbranched saturated and unsaturated hydrocarbon chain like “alkyl” and “alkeylene”. Examples of alkyl include methyl, ethyl, n-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and so on. Examples of alkylene include methylene (-CH2-), ethylene (-CH2CH2-), isopentylene (-CH2-CH(CH3-)-CH2-CH2-), n-octylene (-(CH2)8-) and so on.

Typically, POE-IV based copolymers or TEG-POE IV is synthesized using a step-growth polymerization. Important factors that influence the molecular weights of polymers via step-growth polymerizations are the stoichiometric ratios of the monomers used in the polymerization step, the purity of the chemical resources, reaction conditions, and the degree of polymerization. Impurities present in the monomer or reaction solvent has been cited as the most common limitations for achieving high degree of polymerization in step-growth polymerization process. In this invention, we ensure high purity of all materials utilized as all monomers and solvents were purified by recrystallization or distillation techniques (as needed and as suitable). Ideally, the stoichiometric equivalence for two bifunctional monomers, A-A and B-B, should be 1.0. However, through our method, it was discovered that on using higher stoichiometric ratio of one of the bifunctional monomers in certain cases favored a higher degree of polymerization thereby resulting in a high molecular weight TEG-POE IV.
Following the general polymerization procedures, this single-pot method also works to generate other functional analogs to TEG-POE IV wherein the TEG-GL linker can be modified to TEG-LA linker or TEG-GL-LA or LA-TEG-GL followed by in-situ same pot polymerization to obtain various functional derivatives of TEG-POE IV polymers. Similar to TEG-POE IV, the Mw of these polymers increased with increase of DETUSO/Diol content in the polymerization reactions.

Following the general polymerization procedures, this single-pot method also works to generate a wide variety of functional analogs to TEG-POE IV wherein instead of TEG, other diol systems including but not limited to 1.6-hexane diol, 1,10-decane diol and trans-cyclohexanedimethanol (t-CDM) were used. The Mw of these type of polyorthoesters (POE IV) also greatly depended on DETUSO/Diol content in the polymerization reactions.

According to the present invention, the polymer comprising of the following two structural units:

R is a C1-C12 alkyl, preferably C2-C10 alkyl, and more preferably C2 alkyl;
i is between 1-10, preferably 2-8, more preferably i = 3-5;
m is between 5 and 100, preferably between 10 and 60, and more preferable between 15 and 40;
n is between 1 and 40, preferably between 4 and 60, and more preferable between 8 and 25;
x is between 0 and 12, preferably between 1 and 7, and more preferable between 2 and 4;
y is between 0 and 12, preferably between 1 and 7, and more preferable between 2 and 4;
x+y is between 1 and 24, preferably between 1 and 10, and more preferable between 2 and 4;
m/n is between 1 and 25; preferable between 1 and 10, and more preferable between 1 and 5;

The polymer has a weight-average molecular weight (Mw) between 1500 Da to 70000 Dalton, preferably in the range 3500 Dalton to 30000 Dalton, and more preferably in the range 5000 Dalton to 20000 Dalton;

The polydispersity index (PDI) of the polymers is in the range of 1.05 to 4.5, preferably in the range 1.1 to 3.2, more preferably in the range 1.15 to 2.8.

The terminologies used in this present disclosure such as “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise.

The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range 10 of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4. The term “wt. %” means weight percent. The term “w/w” means weight per weight. The term “weight average molecular weight (Mw)” means a measuring system of the polymer weight that includes the mass of individual chains, which contributes to the overall molecular weight of the polymer.

The term “latent acid” means short acid segments in the polymer backbone, such as glycolic acid, lactic acid et al. The term “reaction feeding or feed ratio” means the molar ratio of used DETOSU monomer to the total of triethylene glycol and triethylene glycol-glyolic acid.

The term “polyol” refers to a chemical compound having more than one hydroxy (-OH) functional group. The term “diol” refers to a chemical compound having two hydroxy (-OH) groups.

The term “alkyl” refers a branched or unbranched saturated hydrocarbon chain with one carbon atom to the number of carbon atoms designated (e.g., C1-C14 alkyl). Examples of alkyl include methyl, ethyl, n-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and so on. The term “alkylene' refers to a branched or unbranched saturated hydrocarbon chain with one carbon atom to the number of carbon atoms designated (e.g., C1-C14 alkylene). Examples of alkylene include methylene (-CH2-), ethylene (-CH2CH2-), isopentylene (-CH2-CH(CH3-)-CH2-CH2-), n-octylene (-(CH2)8-) and so on.

Typically, POE-IV based copolymers or TEG-POE IV is synthesized using a step-growth polymerization. Important factors that influence the molecular weights of polymers via step-growth polymerizations are the stoichiometric ratios of the monomers used in the polymerization step, the purity of the chemical resources, reaction conditions, and the degree of polymerization. Impurities present in the monomer or reaction solvent has been cited as the most common limitations for achieving high degree of polymerization in step-growth polymerization process. In this invention, we ensure high purity of all materials utilized as all monomers and solvents were purified by recrystallization or distillation techniques (as needed and as suitable). Ideally, the stoichiometric equivalence for two bifunctional monomers, A-A and B-B, should be 1.0. However, through our method, it was discovered that on using higher stoichiometric ratio of one of the bifunctional monomers in certain cases favored a higher degree of polymerization thereby resulting in a high molecular weight TEG-POE IV.

In certain embodiments, oxygen, moisture (or both) is excluded during the reaction processes via inert gas purging or vacuum or both or performing the reaction inside a glove box. A mixture of glycolic acid and diol linker are mixed and dissolved in pure organic solvent and allowed to stir at high temperature without the use of any catalyst for a certain amount of time.

Typical preferred reaction temperature for synthesis of linker is ~120 oC. After certain amount of time, the reaction mixture is allowed to come to room temperature and the monomers (or monomer solutions separately prepared) are added to the same reaction mixture in the same pot at room temperature followed by addition of catalyst.

Typical preferred reaction temperature for complete conversion of monomer mixtures to the final polymer was found to be room temperature (25 °C). However, both the steps were carefully and diligently monitored over a time necessary for complete conversion to the desired respective products.

According to another embodiment the final purified polymer product is obtained after filtration followed by repeated re-precipitation in an antisolvent and vacuum drying. Molecular weight of synthesized polymer was characterized with gel permeation chromatography (GPC).

The present invention was tested using Gel permeation chromatography (GPC)Test, performed on Waters HPLC system with a refractive index detector (2414) utilizing Shodex GPC KF-804 column (Length 300 mm, ID8.0mm) (elution range 7 kDa – 120 kDa). Merck, HPLC grade THF was used as the eluent at a flow rate of 1.0 mL/min at 40°C. The molecular weight calibration was performed with monodisperse linear polystyrene (0.6 kDa to 300 kDa). For molecular weights, the entire signal of a major peak including its shoulder at a lower retention volume was integrated.

According to the present invention, we state to clarify that the overall conclusions obtained through our experiments and observations and the concepts developed through the detailed studies described herein are not limited to specific processes, compounds, products, synthetic methods, articles, devices, or uses as such which can of course vary and can be utilized in much broader aspects or fields. Also, it is expected to be understood that the terminologies used herein are meant to describe particular aspects only, and unless specifically defined herein, are not intended to be limiting.

Unless otherwise stated, all technical and scientific terminologies used in this present invention disclosure have the same meaning as commonly understood by one with ordinary skill in the art. In case of any conflict, the present document will clearly specify the contexts including definitions. Details of the preferred methods and materials used and developed herein are described below. However, any other methods and materials similar or equivalent in their reactivity and quality to those described herein can be in principle used for testing the present invention.

The following examples as described below illustrates the present invention as claimed. These examples are only intended as possible methods without limiting the invention to their contents.

EXAMPLES

Example 1: TEG-POE IV (TEG: TEG-GA)

Preparation of the DETOSU monomer:

600 mL of Ethylenediamine was added into a round bottomed flask under inert atmosphere, to which 175 gm of potassium tert-butoxide was added. After the reaction mass was dissolved, 100 gm of 3,9-Divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane (DVTOSU) was added to the reaction mass at room temperature. Gradually, the temperature was raised to 120oC and maintained for 30 hours. Reaction mass was turned colorless to brown color, during the course of reaction. The reaction completion was monitored with the help of TLC.

After completion of reaction, the reaction mass was brought to room temperature and 1000 ml hexane was added. Then, the reaction mass was poured into chilled water and the compound was extracted into organic layer, followed by repeated washing with water to remove impurities. Organic compound was then dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude product which was purified by distillation followed by crystallization in hexane at -20 oC to obtain the pure product as white solid (60% yield).

General Method for Single pot reaction for synthesis of latent-acid linker followed by in-situ polymerization to obtain TEG-POE IV polymer

900 mg of Glycolide and 5.75 gm of triethyleneglycol were added to a flame dried round bottom flask under inert atmosphere. The temperature of the reaction mixture was gradually raised to 120oC and the reaction mixture was stirred at 120oC temperature for 24-48 hours. The completion of the reaction was monitored with the help of TLC. After completion of the reaction, the temperature of the reaction was cooled to room temperature and 20 ml of freshly distilled THF was added to the reaction mixture and stirred under inert atmosphere for 1 hour. To this reaction mixture, 10 gm of DETOSU which is dissolved in 50 ml of dry THF was slowly added under inert atmosphere. Then 2-3 drops of p-TSA solution (Conc.:10 mg of PTSA in 1 ml dry THF) was added to the above reaction mass and stirred for 2 hours at 30oC under inert atmosphere. After completion of the reaction, reaction mass obtained from the single-pot from two consecutive reactions was slowly added to 300 ml of vigorously stirred dried hexane under inert atmosphere. The polymerized product was observed as a sticky colorless precipitate at the bottom of the flask. After complete precipitation, the hexane layer was decanted and the polymer precipitate was dissolved in dry THF and reprecipitated into hexane. The reprecipitation process was repeated for 3 times to remove all the unwanted unreacted impurities from the polymer. The purified polymer was dried under reduced pressure under high vacuum pump to give a colorless highly viscous TEG-POE IV polymer (50% yield).

Characterization:

Molecular weight of synthesized polymer was characterized with gel permeation chromatography (GPC). Test was performed on Waters HPLC system with a refractive index detector (2414) utilizing Shodex GPC KF-804 column (Length 300 mm, ID8.0mm) (elution range 7 kDa – 120 kDa). Merck, HPLC grade THF was used as the eluent at a flow rate of 1.0 mL/min at 40°C. The molecular weight calibration was performed with monodisperse linear polystyrene (0.6 kDa to 300 kDa). For molecular weights, the entire signal of a major peak including its shoulder at a lower retention volume was integrated.

Table 1. Control in TEG-POE IV molecular weights (Mw) with respect to change in DETUSO: Diol ratio

S. No DETOSU/Diol Ratio Weight Average Molecular Weights (Mw) Number Average Molecular Weights (Mn) PDI
1 1.0 3242 1955 1.7
2 1.2 5382 3010 1.8
3 1.4 10671 5013 2.1
4 1.6 14371 5285 2.7

Example 2: TEG-POE IV

Preparation of the DETOSU monomer:

800 mL of Ethylenediamine was added into a round bottomed flask under inert atmosphere, to which 200 gm of potassium tert-butoxide was added. After the reaction mass was dissolved, 130 gm of 3,9-Divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane (DVTOSU) was added to the reaction mass at room temperature. Gradually, the temperature was raised to 120oC and maintained for 30 hours. Reaction mass was turned colorless to brown color, during the course of reaction. The reaction completion was monitored with the help of TLC.

After completion of reaction, the reaction mass was brought to room temperature and 1000 ml hexane was added. Then, the reaction mass was poured into chilled water and the compound was extracted into organic layer, followed by repeated washing with water to remove impurities. Organic compound was then dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude product which was purified by distillation followed by crystallization in hexane at -20 oC to obtain the pure product as white solid (62% yield).

General Method for Single pot reaction for synthesis of latent-acid linker followed by in-situ polymerization to obtain TEG-POE IV polymer

1000 mg of Glycolide and 8 gm of triethyleneglycol were added to a flame dried round bottom flask under inert atmosphere. The temperature of the reaction mixture was gradually raised to 120oC and the reaction mixture was stirred at 120oC temperature for 5-8 hours. The completion of the reaction was monitored with the help of TLC. After completion of the reaction, the temperature of the reaction was cooled to room temperature and 40 ml of freshly distilled THF was added to the reaction mixture and stirred under inert atmosphere for 1 hour. To this reaction mixture, 15 gm of DETOSU which is dissolved in 80 ml of dry THF was slowly added under inert atmosphere. Then 4 drops of p-TSA solution (Conc.:10 mg of PTSA in 1 ml dry THF) was added to the above reaction mass and stirred for 2 hours at 30oC under inert atmosphere. After completion of the reaction, reaction mass obtained from the single-pot from two consecutive reactions was slowly added to 500 ml of vigorously stirred dried hexane under inert atmosphere. The polymerized product was observed as a sticky colorless precipitate at the bottom of the flask. After complete precipitation, the hexane layer was decanted and the polymer precipitate was dissolved in dry THF and reprecipitated into hexane. The reprecipitation process was repeated for 3 times to remove all the unwanted unreacted impurities from the polymer. The purified polymer was dried under reduced pressure under high vacuum pump to give a colorless highly viscous TEG-POE IV polymer (55% yield).
,CLAIMS:CLAIMS:

1) A single-pot process, for the preparation of POE-IV based copolymers including TEG-POE IV based copolymers, which is carried out by preparing the latent acid diol linker followed by in-situ polymerization reaction.

2) A process for preparing polymers POE IV polymers represented in Formula II comprising the steps of

Formula II

(a) dissolving excess TEG (or any dihydroxy alkyl compounds) and glycolide in an organic solvent at elevated temperatures under inert atmosphere to form the latent acid hydroxy-based linkers;
(b) dissolving DETOSU monomer in an organic solvent to form a separate monomer solution;
(c) after formation of the latent acid hydroxy-based linker in step a, adding the DETUSO monomer solution to start the polymerization reaction; and
(d) stirring the solutions under inert atmosphere and high speed to produce polymer.

3) A process for preparing polymer TEG POE- IV represented in Formula II comprising the steps of

Formula III
wherein n is between 5 and 35.

(a) dissolving excess TEG and glycolide in an organic solvent at elevated temperatures under inert atmosphere to form the glycolic acid diol linker;

wherein m is between 2 and 7.

(b) dissolving DETOSU monomer in an organic solvent to form a separate monomer solution;

(c) after formation of the latent acid hydroxy-based linker in step a, adding the DETUSO monomer solution to start the polymerization reaction; and

wherein m is between 2 and 7; n is between 3 and 40; p is between 15 and 100.

(d) stirring the solutions under inert atmosphere and high speed to produce polymer.

4) According to the claim 1, 2 and 3, the polymer has a weight-average molecular weight (Mw) between 1500 Da to 70000 Dalton, preferably in the range 3500 Dalton to 30000 Dalton, and more preferably in the range 5000 Dalton to 20000 Dalton;
5) According to the claim 1, 2 and 3, the polydispersity index (PDI) of the polymers is in the range of 1.05 to 4.5, preferably in the range 1.1 to 3.2, more preferably in the range 1.15 to 2.8.
6) According to the claim 1, 2 and 3, the process covers for preparing the polymer with molecular weights ranging from 3kDa to 70kDa.
7) According to the claim 1, 2 and 3, the feed ratio between DETOSU to the total amount of diol and diol-glycolic acid; or diol and diol-lactic acid; or diol and diol-glycolic acid-lactic acid is between 0.5 to 2.2.